Field of the Invention
The present invention relates to a composition and a fusion protein for prevention or treatment of autoimmune diseases, which contain a Smad protein, and provides a method for prevention or treatment of autoimmune diseases, including lupus nephritis and rheumatoid arthritis.
Description of the Related Art
The human immune system functions to protect the body from foreign antigens, but does not attack self-tissue due to self-tolerance. However, when the self-tolerance of the immune system is broken, immune cells may recognize, as foreign objects, proteins that are normally expressed by their genes, to produce antibodies or cause T-cell responses, thereby destroying normal tissue. This process is referred to as “autoimmune”, and specific symptoms caused by this process are referred to as “autoimmune diseases”.
In the mid-1980s, Mosmann et al. reported that helper T lymphocytes (Th) could be classified into two subsets (Th1 and Th2), based on their pattern of cytokine secretion (Mosmann T R, et al., J Immunol., 136:2348-2357, 1986). Since then, it has been known that Th1 cells secrete IFN-γ and activate macrophages and the like to induce cellular immune responses, and Th2 cells secrete IL-4, IL-5 and the like and are involved in humoral immune responses.
In addition, it is known that excessive differentiation into Th1 cells due to an imbalance between Th1 cells and Th2 cells induces inflammatory autoimmune diseases. However, as it was reported that mice lacking IFN-γ or IFN receptors suffer from autoimmune diseases such as rheumatoid arthritis and multiple sclerosis, doubt on the Th1/Th2 paradigm was cast (Infante-Duarte C, et al., J Immunol., 165: 6107-6115, 2000). Furthermore, studies on IL-12 and IL-23 revealed that Th17 cells induced by IL-23 are more important in causing autoimmune diseases than Th1 cells (Murphy K M, et al., Nat Rev Immunol 2(12):933-44, 2002; Cua D J, et al., 421(6924):744-8, 2003; Langrish C L, et al., J Exp Med 201(2):233-40, 2005).
Th17 cells were named because the T cells induced by IL-23 secrete IL-17 cytokine. It was found that these Th17 cells are distinct from Th1 or Th2 cells. As the Th17 cell transcription factor RORγt was recently identified, signal transduction pathways or transcription processes in Th17 cells were established.
In addition, it is known that, unlike Th1, Th2 and Treg (regulatory T) cells, Th17 cells are involved in the forefront of inflammatory responses appearing in autoimmune diseases and maximize inflammatory response signals to accelerate the progression of the disease. Thus, the development of autoimmune disease therapeutic agents that target the inhibition of Th17 cell activity is attracting a great deal of attention.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that causes inflammation of various organs, including the skin, joints, kidneys, lungs and nervous system, due to abnormalities in the immune system that protects the human body from foreign invaders. A serious complication of systemic lupus erythematosus, which attacks kidneys to reduce renal function, is lupus nephritis (LN).
Although many different immunologic and nonimmunologic factors contribute to disease expression in lupus nephritis, the production of pathogenic autoantibodies against nuclear and endogenous antigens, the formation of glomerular immune deposits and the activation of complement cascades are typically initial events.
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by polyarthritis. In rheumatoid arthritis, inflammation occurs in the intra-articular synovium while erythrocytes in blood are localized to joints. As a result, joint fluid increases, joints swell to cause pain, and inflammatory synovial tissue gradually grows to penetrate bone and cartilage to deform joints, thus hindering joint movement.
The autoimmune disease rheumatoid arthritis characterized by systemic complications, including progressive damage to joints and cardiovascular diseases, results in the loss of immune tolerance due to citrullination caused by environmental or genetic factors. Responses to citrulline are observed in T cells and B cells and appear secondarily in lymphatic tissue or marrow. In addition, intra-articular synovitis in rheumatoid arthritis forms a positive feedback loop by various inflammatory cells and inflammatory substances, and thus can cause continuous inflammation and systemic complications.
Methods for treatment of lupus nephritis and rheumatoid arthritis have dramatically changed, and thus new therapeutic drugs have been continuously developed, and various therapeutic methods, including single methods and combined methods, have been studied. Despite such continuous studies, curative treatment of lupus nephritis and rheumatoid arthritis is still difficult.
Accordingly, the present inventors have attempted to develop a method for treatment of autoimmune diseases, which has high target specificity and also has minimized side effects due to non-cytotoxicity, by use of a specific protein group which is involved in immune system signaling.